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Drug Reference

warfarin

Vitamin K antagonist· Brands: Coumadin, Marevan, Jantoven, WaranPO

Mechanism of action
Warfarin inhibits vitamin K epoxide reductase, an enzyme involved in the recycling of vitamin K. This reduces the synthesis of clotting factors II, VII, IX, and X, as well as the anticoagulant proteins C and S, leading to an anticoagulant effect that takes 2 to 3 days to fully develop.
Pharmacokinetics
Warfarin is well absorbed from the gastrointestinal tract and is highly bound to plasma albumin. Its metabolism occurs mainly via CYP2C9, with genetic variations affecting dose requirements. The elimination half-life is approximately 40 hours, with clearance via the liver and urinary excretion of metabolites. The anticoagulant effect is delayed until the existing clotting factors are depleted.
Indications & dosing

Thromboprophylaxis in atrial fibrillation

Adjust to maintain INR 2-3. Initiate at 5 mg daily if not on prior therapy.

  • adult · PO: 2–10 mg once daily · Adjust to maintain INR 2-3. Initiate at 5 mg daily if not on prior therapy.

Treatment of deep vein thrombosis (DVT)

Adjust to maintain INR 2-3. Usually given after initial parenteral anticoagulation.

  • adult · PO: 2–10 mg once daily · Adjust to maintain INR 2-3. Usually given after initial parenteral anticoagulation.

Treatment of pulmonary embolism (PE)

Adjust to maintain INR 2-3. Overlap with parenteral anticoagulation for at least 5 days.

  • adult · PO: 2–10 mg once daily · Adjust to maintain INR 2-3. Overlap with parenteral anticoagulation for at least 5 days.

Thromboprophylaxis in mechanical heart valve prosthesis

Adjust to maintain INR 2.5-3.5 depending on valve type and position.

  • adult · PO: 2–10 mg once daily · Adjust to maintain INR 2.5-3.5 depending on valve type and position.
Contraindications & precautions
  • Pregnancy · Teratogenic; risk of fetal haemorrhage and skeletal abnormalities.
  • Active bleeding · Warfarin will exacerbate bleeding; use alternative if possible.
  • Severe hepatic impairment · Increases risk of bleeding due to impaired clotting factor synthesis.
  • Recent CNS surgery or haemorrhagic stroke · High risk of intracranial bleeding.
  • Uncontrolled severe hypertension · May increase risk of intracranial haemorrhage.
  • Haemorrhagic disorders · Existing bleeding diathesis.
  • Monitor INR regularly and adjust dose accordingly.
  • Avoid concurrent use of other anticoagulants or antiplatelet agents unless specifically indicated.
  • Exercise caution with many drug interactions; check all new medications, including over-the-counter products.
  • Advise patient to report any signs of bleeding, such as bruising, epistaxis, or melaena.
  • Consider genetic testing for CYP2C9 and VKORC1 polymorphisms when individualising therapy.
  • Maintain a consistent intake of dietary vitamin K.
Adverse effects
  • Bleeding (e.g., gastrointestinal, intracranial, retroperitoneal)serious
  • Skin necrosisserious
  • Purple toe syndromeserious
  • Teratogenicityserious
  • Nausea and vomiting
  • Hair loss (alopecia)
  • Liver dysfunctionserious
Interactions
  • carvedilolminorMonitor INR closely when initiating, discontinuing, or changing the dose of carvedilol in patients taking warfarin. Perform a repeat INR within 3–5 days of any change and adjust the warfarin dose accordingly. Advise patients to report signs of bleeding.
  • apixabancontraindicatedCo-prescription is contraindicated. If switching therapy, discontinue one agent and start the other according to an accepted transition protocol, with close monitoring of INR and clinical bleeding signs. Do not overlap the agents except during supervised switching.
  • dabigatranmajorAvoid co-prescription. When switching from warfarin to dabigatran, stop warfarin and wait until the International Normalised Ratio (INR) is below 2.0 before starting dabigatran (for most indications). When switching from dabigatran to warfarin, start warfarin while continuing dabigatran for 2–3 days, then stop dabigatran and adjust warfarin dose based on INR. However, this is not routine practice and should follow local guidance.
  • prednisolonemajorMonitor the INR frequently, particularly within the first 2-3 days after initiating or stopping prednisolone, and adjust the warfarin dose accordingly. Consider adding a gastroprotective agent (e.g., a proton pump inhibitor) in patients at increased risk of gastrointestinal bleeding. Advise patients to report any signs of bleeding, such as easy bruising, dark stools, or haematuria.
  • clarithromycinmajorAvoid co-prescription if possible. If no suitable alternative antibiotic is available, closely monitor the INR, particularly during the first week of concurrent therapy, and adjust the warfarin dose as necessary. Continue monitoring for a few days after stopping clarithromycin.
  • amoxicillinmoderateMonitor INR closely, particularly within the first week of concurrent therapy. Consider more frequent INR checks and adjust warfarin dose as needed. Advise patient to report signs of bleeding.
  • ibuprofenmajorAvoid concurrent use if possible. Prefer paracetamol or a short course of a proton pump inhibitor plus a less gastrotoxic NSAID if an NSAID is essential. If no alternative exists, use the lowest effective dose of ibuprofen for the shortest duration, monitor INR within 3 to 5 days of initiation and regularly thereafter, and watch for signs of bleeding. Prescribe gastroprotection with a proton pump inhibitor.
  • omeprazolemoderateMonitor INR closely, especially when starting or stopping omeprazole. Consider alternative acid-suppressant therapy with a proton pump inhibitor that has less CYP2C9/2C19 interaction (e.g., pantoprazole) if appropriate. Adjust warfarin dose as required.
  • paracetamolmoderateIf paracetamol is required, it is advisable to use the lowest effective dose for the shortest duration. Monitor the INR within 3 to 5 days after starting or stopping paracetamol, and regularly during concurrent use (e.g., every 1 to 2 weeks). Consider alternative analgesics if the INR rises significantly or if bleeding occurs. Ensure patient education about signs of bleeding.
  • fluconazolemajorPrescribers should avoid co-prescribing fluconazole with warfarin when possible. If concurrent use is unavoidable, a reduction in the warfarin dose may be required, and the INR must be monitored closely, especially during the first week of combined therapy and after any change in fluconazole dose. Alternative antifungal agents that do not inhibit CYP2C9 should be considered.
  • metronidazolemajorAvoid concomitant use if possible. If co-administration is necessary, monitor the INR frequently (e.g., every 2 to 3 days) for the first week of metronidazole therapy and for several days after discontinuation, and adjust the warfarin dose accordingly to maintain the target INR. Consider using an alternative antibiotic with no known interaction (e.g., a penicillin or macrolide, depending on the infection). Educate the patient about signs of bleeding and the need for prompt medical review.
  • levothyroxinemajorMonitor INR closely (e.g., weekly) when levothyroxine is initiated, discontinued, or the dose is changed. Adjust the warfarin dose as needed to maintain the target INR. Advise patients to report signs of bleeding.
  • phenytoinmajorAvoid co-prescription if possible. If necessary, monitor INR frequently and adjust warfarin dose accordingly. Monitor serum phenytoin levels and signs of toxicity, adjusting phenytoin dose as needed. Consider alternative anticonvulsants or anticoagulants that do not interact (e.g., levetiracetam for seizures, or a DOAC if appropriate).
  • ciprofloxacinmajorPrescribers should avoid concurrent use if possible, especially in patients with other bleeding risk factors. If co-prescription is necessary, closely monitor the INR at baseline, after 2 to 3 days, and then regularly throughout treatment. Adjust the warfarin dose as needed and warn the patient to seek medical attention if signs of bleeding occur.
  • clopidogrelmajorAvoid concomitant use unless the benefit clearly outweighs the bleeding risk and no alternative exists. If combination therapy is considered essential, use the shortest possible duration, monitor INR frequently, and closely observe for signs of bleeding. Consider gastroprotection with a proton pump inhibitor (e.g., omeprazole or pantoprazole) in patients at risk of gastrointestinal bleeding. If invasive procedures or surgery are planned, the combination should be stopped appropriately in advance.
  • azithromycinmajorIf co-administration is necessary, monitor INR frequently (e.g., within 3-5 days of starting or stopping azithromycin) and adjust warfarin dose as needed. Consider alternative antibiotics with lower interaction potential. Advise patients to report signs of bleeding.
  • carbamazepinemajorMonitor INR closely, typically within 3 to 5 days of starting or stopping carbamazepine, and adjust the warfarin dose accordingly. Consider an alternative antiepileptic that does not induce hepatic enzymes if possible. Advise patients to report signs of thrombosis or bleeding. When carbamazepine is stopped, the warfarin dose will likely need to be reduced to avoid excessive anticoagulation.
  • rifampicinmajorAvoid co-prescription where possible. If combination is unavoidable, anticipate a two- to threefold increase in the warfarin dose and monitor INR closely, particularly during the first week of rifampicin therapy and again after rifampicin is stopped. Consider alternative antibiotics with less enzyme-inducing potential or consider alternative anticoagulation strategies, such as a direct oral anticoagulant, where appropriate.
  • diclofenacmajorAvoid co-prescription where possible. If the combination is necessary, use the lowest effective dose of diclofenac for the shortest duration and consider gastroprotection with a proton pump inhibitor. Monitor INR closely (e.g., more frequently than usual) and watch for signs of bleeding. Consider alternative analgesics such as paracetamol or opioid-based analgesia.
  • erythromycinmajorAvoid concomitant use if possible. If co-prescription is necessary, monitor the INR closely at baseline and within 3 to 5 days of starting erythromycin. Consider a reduction in warfarin dose and continue monitoring after erythromycin is stopped.
  • sulfasalazinemajorIf co-prescription is necessary, monitor INR frequently, especially after starting or stopping sulfasalazine. Consider reducing the warfarin dose to maintain the target INR. Advise the patient to report signs of bleeding such as bruising, black stools, or blood in urine. Alternative therapy with less interaction potential may be considered.
  • aspirinmajorAvoid combined use where possible, especially in patients with a high baseline bleeding risk or those requiring prolonged therapy. If the combination is necessary, use the lowest effective aspirin dose, consider gastroprotection with a proton pump inhibitor, and monitor INR more frequently. Educate the patient on signs of bleeding and advise prompt medical review if they occur.
  • flucloxacillinmajorMonitor INR closely before, during, and after co-prescribing flucloxacillin. Consider a reduced warfarin dose or more frequent INR checks, particularly in the first week. Advise patients to report any signs of bleeding. If flucloxacillin is stopped, INR may fall, requiring dose adjustment.
  • naproxenmajorAvoid co-prescription where possible. If the combination is essential, use the shortest possible duration of naproxen, monitor INR at least weekly, and consider adding gastroprotection (e.g., a proton pump inhibitor). Counsel the patient to report any symptoms of bleeding. Alternative analgesics such as paracetamol may be preferred.
  • levofloxacinmajorIf co-prescription is necessary, monitor INR frequently (e.g., every 2-3 days) during the first week of levofloxacin therapy and for at least one week after stopping. Consider reducing warfarin dose based on INR. Advise patients to report any signs of bleeding.
  • trimethoprimmajorAvoid co-prescription if an alternative antibiotic is suitable. If the combination is unavoidable, monitor INR more frequently (e.g., before starting, then 3–5 days later, and as needed), and consider a prophylactic warfarin dose reduction. Advise the patient to report signs of bleeding.
  • amiodaronemajorAvoid the combination if possible. If concurrent use is necessary, reduce the warfarin dose, typically by 30-50%, and monitor INR frequently (at least weekly) during the first few weeks of therapy and after any dose change. Continue to monitor INR for several weeks after amiodarone is stopped, as its effects are prolonged. Consider alternative antiarrhythmic agents where appropriate.
  • fluoxetinemajorAvoid concurrent use if possible. If combined, monitor the international normalised ratio closely for at least two weeks after starting fluoxetine and after any dose change, and adjust warfarin dose accordingly. Review the patient for signs of bleeding and consider alternative antidepressants with less interaction potential.
Renal & hepatic adjustment
  • Hepatic impairment (moderate): Reduce initial dose and monitor INR frequently.
  • Hepatic impairment (severe): Avoid use; increased risk of bleeding. (avoid)
Monitoring, pregnancy & toxicity
  • INR (international normalised ratio) · At least twice weekly initially, then every 2 to 4 weeks when stable
  • Signs of bleeding · At each review
  • Haemoglobin · Periodically, especially if bleeding is suspected
  • Pregnancy: Warfarin is contraindicated in pregnancy due to teratogenicity; when anticoagulation is essential, use an alternative such as heparin. Exceptional cases (e.g. mechanical heart valves) may warrant specialist advice.
  • Toxicity: Bleeding (e.g. bruising, epistaxis, intracranial haemorrhage) · Withdraw warfarin; give intravenous vitamin K. For major bleeding, give prothrombin complex concentrate or fresh frozen plasma.
  • Toxicity: Over-anticoagulation (INR above therapeutic range) · In asymptomatic patients, withhold warfarin and give vitamin K depending on INR; monitor and restart when INR in range.
Antidotes & reversal
  • Vitamin K (phytomenadione) with 4-factor PCC · Vitamin K (10 mg slow IV) plus 4-factor prothrombin complex concentrate for major bleeding.
Clinical notes
Warfarin requires regular monitoring of the International Normalised Ratio (INR) and dose adjustment. It has many interactions with drugs, foods, and herbal products. The antidote is vitamin K (phytomenadione) and, in severe bleeding, prothrombin complex concentrate. Avoid in pregnancy, except in mechanical heart valves, because of teratogenic effects. Consider alternative anticoagulants in patients with poor venous access or compliance issues.

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BNF; local formulary